Leprosy and leishmaniasis have many similarities, in that both diseases form a clinical spectrum that correlates with cell mediated immune responsiveness and represent important problems in developing countries. This proposal derives from a longstanding collaborative research effort on leprosy which we hope to extend to American cutaneous leishmaniasis as well. A number of fundamental approaches to understanding the nature of protective antigens of M. leprae and Leishmania species are proposed, with particular emphasis on using molecular biological approaches to obtaining new and specific antigens recognized at the T cell level. A major effort will be made to understand the mechanisms of immunoregulation in the spectra of leprosy and leishmaniasis, defining T cell subsets and functions in lesions, and developing clones of Th, Tc and Ts cells. Combination vaccines composed of BCG given together with killed M. leprae or Leishmania promastigotes have had remarkable therapeutic effects in lepromatous leprosy and localized leishmaniasis. Therapeutic trials to compare the efficacy of immunotherapy in patients infected with different Leishmanial species, with different forms of the disease and in different regions will be made, and immunoregulatory changes brought about by successful immunization will be analyzed. Finally, a detailed epidemiologic study of Leishmaniasis in Venezuela will be carried out that will serve as the basis for a proposed vaccine trial comparing the efficacy of combined vaccines containing BCG and L. mexicana and L. braziliensis, relative to BCG alone in protecting against cutaneous leishmaniasis.